AID hits the jackpot when missing the target

Abstract

Activation induced deaminase is the single B cell specific factor mediating class switch recombination and somatic hypermutation. Numerous studies have shown that AID preferentially targets Ig substrates and also attacks non-Ig substrates to create DNA damage that contributes to lymphomagenesis. AID targeting to Ig loci is linked to transcription but the mechanism governing this process has been obscure. Here we discuss research that illustrates the connection between AID targeting to DNA substrates and transcription processes to reveal rules governing the specificity of AID attack. These observations are woven together to provide a integrated view of AID function and a surprising linkage with global regulation of gene expression.

Figure 1. The looping-out and deletion model of Ig switch recombination

A) A partial schematic map of Igh locus before CSR is shown not to scale. A productive V(D)J rearrangement has occurred allowing expression of the γ and ^™ IgH chains. Intact Sμ and Sγ1 are separated by approximately 70 kb. Stimulation of B cells with antigen or mitogen induces germline transcription through the Iγ1-Sγ1-Cγ1 region prior to recombination. B) The Sμ and Sγ1 regions are aligned causing the intervening genomic DNA to form a loop. C) A reciprocal crossover between Sμ and Sγ1 results in the formation of a new hybrid transcriptional unit containing the original VDJ exons contiguous with Cγ1 and the formation of hybrid Sμ/Sγ1 molecules. D) A schematic diagram depicts a generic I-S-C_H region downstream of the GLT promoter (Pr). Above the diagram a summary of mutation frequencies 5′ and 3′ of the S region is shown.